Process for the selective oxidation of alcohols using readily removable nitroxyl radicals

ABSTRACT

The invention relates to a process for the selective oxidation of alcohols to ketones or to aldehydes by means of an alkali hypohalite under alkaline conditions, which comprises carrying out the oxidation in the presence of a heterogeneous oxidation catalyst that is insoluble in the reaction medium and is selected from the group comprising the compounds of formula (I)  
                 
 
                 
 
     (III), wherein n is a number from 3 to 3000; or a 4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl that is 4-oxy-bound to a Merrifield polymer. The invention relates also to the compounds of formulae (II) and (III) and to the use of the above-mentioned oxidation catalysts for the oxidation of alcohols.

[0001] The invention relates to a process for the selective oxidation ofalcohols to aldehydes and to ketones using a readily removableheterogeneous oxidation catalyst based on a nitroxyl radical, and usingan alkali hypohalite as oxidising agent.

[0002] Alcohols are one of the most important building blocks in organicsynthesis. An extensive arsenal of preparative methods for producingthem make primary and secondary alcohols ideal preliminary stages forthe synthesis of aldehydes, ketones and carboxylic acids. Customaryoxidising agents are heavy metal reagents, for example chromium(VI)compounds, lead(IV) compounds and ruthenium, manganese and vanadiumcompounds, peracids, activated dimethyl sulfoxide (DMSO) and hypervalentiodine compounds.

[0003] Selectivity is of primary importance in such oxidation processes.Further functional groups present in the molecule, such as, for example,double bonds, should generally not be affected under the conditionschosen. Often, the targeted oxidation of secondary alongside primaryalcohol functions or vice versa is desired, without the respective otherfunction being affected. In the synthesis of aldehydes from primaryalcohols, carboxylic acids are often formed as by-products of theoxidation reaction (over-oxidation), and the oxidation of 1,2-diols orα-hydroxyketones is frequently accompanied by C—C cleavage reactions. Afurther disadvantage of many oxidants is that they are frequentlyrelatively awkward or difficult to prepare or handle;heavy-metal-containing reagents, especially, are moreover in most caseshighly toxic and ecologically very harmful. Finally, however, the costsof an oxidation method are of decisive importance, especially when theintended use is industrial.

[0004] It is known that primary and secondary alcohols can be convertedinto the corresponding carbonyl compounds using aqueous sodiumhypochlorite solution in the presence of catalytic amounts of organicnitroxyl radicals (A. E. J. de Nooy, A. C. Besemer, H. van Bekkum,Synthesis, 1996, 1153).

[0005] Hitherto such reactions—especially when2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) has been used—havepredominantly been carried out in homogeneous phase. The reactions werecarried out either stoichiometrically or catalytically in respect ofTEMPO or the oxidation product resulting therefrom. The working up ofthe reaction products in such processes often proves to be awkward andinvolved, since a great deal of effort is required to remove thecatalyst and its attendant products.

[0006] Oxidation processes that employ immobilised or readily removablenitroxyl compounds have not, however, been described hitherto.

[0007] It has now, surprisingly, been found that alcohols can be reactedwith sodium hypochlorite, as oxidant, to produce the correspondingcarbonyl compounds in good yields by using certainhigher-molecular-weight or oligomeric or polymer-fixed2,2,6,6-piperidin-1-oxyls as catalysts.

[0008] Aliphatic 1,3-diols can be reacted in the presence of an aldehydeor ketone under suitable experimental conditions, in basic medium, toform the corresponding cyclic acetals and ketals (1,3-dioxanes),respectively, directly. 1,5-Diols are reacted to formtetrahydropyran-2-ols or ethers thereof or to formtetrahydropyran-2-ones (δ-valerolactones), according to the experimentalconditions. Hydroxy functions in the a-position to carboxy functions arenot affected.

[0009] Addition of bromide which, in the case of oxidation using ahypochlorite/TEMPO system carried out homogeneously, results in anappreciable acceleration of the reaction (S. D. Rychnovsky, R.Vaidyanathan, J. Org. Chem., 1999, 64, 310), can be dispensed with inthis process without any disadvantage. The merits of the present processlie in the simplified working up of the reaction batches, the repeatedre-use of the catalyst and the omission of bromide asreaction-accelerating additive.

[0010] The invention relates to a process for the selective oxidation ofalcohols to ketones or to aldehydes by means of an alkali hypohaliteunder alkaline conditions, which process comprises carrying out theoxidation in the presence of a heterogeneous oxidation catalyst that isinsoluble in the reaction medium and is selected from the groupcomprising the compounds of formulae (I), (II), (III)

[0011] (III), wherein n is a number from 3 to 3000; or a4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl that is 4-oxy-bound to aMerrifield polymer.

[0012] Preferably, n is a number from 10 to 1000, especially from 10 to500 and more especially from 10 to 100.

[0013] Preference is given to a process that uses as the alkalihypohalite LiOCl, NaOCl, KOCl, LiOBr, NaOBr or KOBr.

[0014] LiOCl, NaOCl and KOCl are especially preferred, NAOCl being moreespecially preferred.

[0015] The oxidising agent is preferably added in the form of an aqueoussolution to the alcohol to be oxidised. The concentration may varywithin a wide range and is preferably from 5% to 20% by weight,especially from 10 to 15% by weight, of active chlorine based on thealcohol to be oxidised.

[0016] Together with the oxidising agent, the aqueous solution can berendered alkaline by means of a base. Preferred bases are aqueoussolutions of alkali or alkaline earth hydroxides, alkali or alkalineearth carbonates and the corresponding hydrogen carbonates.

[0017] Alkali hydrogen carbonates are especially preferred, sodiumhydrogen carbonate being more especially preferred.

[0018] The pH value of the aqueous oxidation solution after the additionof the desired base is in the range from 8 to 12, especially in therange from 9 to 11 and more especially in the range from 9 to 10.

[0019] The alcohol to be oxidised may be liquid or solid. In the case ofliquid alcohols, the reaction can be carried out without the addition offurther solvents, but it can be advantageous to carry out the oxidationin a higher dilution. Solid alcohols always require a suitable organicsolvent.

[0020] Suitable organic solvents or solvent mixtures are those which arewater-immiscible. Examples include aliphatic hydrocarbons, aromatichydrocarbons, chlorinated hydrocarbons or mixtures of such solvents withketones, amides or esters.

[0021] Preferred solvents are aromatic hydrocarbons or mixtures thereofwith ketones. Preferred examples include benzene, toluene and theisomers of xylene, which, if desired, can be mixed with acetone.

[0022] The mixing ratio can be from 10:1 to 2:1, but is preferably from5:1 to 2:1

[0023] Special preference is given to a mixture of toluene and acetonein a ratio of 3:1.

[0024] Preference is given to a process in which a4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl that is 4-oxy-bound to aMerrifield polymer is used.

[0025] So-called Merrifield polymers are known to the person skilled inthe art and are available commercially. In this connection, theMerrifield polymer is chloromethylated polystyrene that is partiallycrosslinked with divinylbenzene and therefore insoluble in conventionalorganic solvents.

[0026] The degree of crosslinking may be, for example, from 1 to 5%, andis typically from 1 to 2%. The particle size can vary within a widerange, and is typically from 100 to 400 mesh. The chlorine content is,for example, from 0.2 to 5 mmollg; common polymers contain from 0.6 to 4mmol/g.

[0027] The Merrifield polymer and the exchange of the chlorine atom canbe represented diagrammatically as follows:

[0028] Preferably, the heterogeneous oxidation catalyst is added in anamount of from 0.1 to 20% by weight, especially from 1 to 10% by weightand more especially from 2 to 6% by weight, based on the alcohol used.

[0029] Preference is given to a process wherein a two-phase solventsystem is used in which one phase is aqueous and comprises the oxidisingagent.

[0030] Suitable solvents and solvent mixtures, including those which arepreferred, have already been described hereinbefore.

[0031] Preferably, the reaction is carried out at a temperature of lessthan 10° C.

[0032] A temperature range of approximately from 0° C. to 10° C. isespecially preferred.

[0033] The preparation of the compounds of formulae (I) to (III) and thepreparation of the modified Merrifield polymer are carried out accordingto methods known per se in accordance with the reaction schemehereinbelow.

[0034] In a first step, compound 3[4-hydroxy-2,2,6,6-piperidin-1-oxyl(4-hydroxy-TEMPO)] is reacted with sodium hydride. 4-Hydroxy-TEMPOitself is available commercially.

[0035] Compound 4 is further reacted in accordance with reaction 2, 3, 4or 5, according to the desired end product.

[0036] The compounds of formulae (II) and (III) are novel and theinvention relates likewise thereto.

[0037] The invention relates also to the use, as a catalyst for theselective oxidation of alcohols to ketones by means of an alkalihypohalite under alkaline conditions, of a compound of formula (I),(II), (III) or a 4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl that is4-oxy-bound to a Merrifield polymer.

[0038] The following Examples illustrate the invention.

EXAMPLES A Preparation of the Oxidation Catalysts EXAMPLE A1

[0039] Preparation of Compound 6.

[0040] In a 500 ml Schlecnk tube, 20 g (113.6 mmol) of 4-hydroxy-TEMPO,compound 3, are dissolved in 200 ml of anhydrous toluene and then 3.34 g(139.2 mmol) of NaH are added thereto in small portions. The reactionbatch is stirred for about 12 hours at room temperature and then asolution of 4.75 g (25.75 mmol) of cyanuric chloride, compound 5, inapproximately 50 ml of toluene is added dropwise thereto. The solutionis stirred first of all at room temperature for 2.5 hours and then atapproximately from 70° C. to 90° C. for 72 hours. After cooling to roomtemperature, the organic phase is washed three times with 100 ml of a10% aqueous solution of Na₂CO₃ each time and then dried over Na₂SO₄. Allvolatile constituents are evaporated off in vacuo at 10⁻² torr and thered oil that remains is recrystallised from a small amount of ethylacetate, yielding 9.3 g (61%) of product in the form of fine orange-redneedles. M.p. 164-166° C. The product is insoluble in H₂O but soluble inCH₂Cl₂, CHCl₃, C₆H₅Cl, toluene and ethyl acetate.

EXAMPLE A2

[0041] Preparation of Compound 8.

[0042] In a 500 ml Schlenk tube, 20 g (113.6 mmol) of 4-hydroxy-TEMPO,compound 3, are dissolved in 200 ml of anhydrous THF and then 3.34 g(139.2 mmol) of NaH are added thereto in small portions. The reactionbatch is stirred for about 12 hours at room temperature and then asolution of 6.26 g (18 mmol) of hexachlorocyclotriphosphazene, compound7, in approximately 50 ml of THF is added dropwise thereto and thereaction mixture is heated under reflux at 70° C. for approximately 24hours. After cooling to room temperature, the volatile constituents areevaporated off in vacuo (approximately 10⁻² torr) and the residue isdissolved in 100 ml of CH₂Cl₂. The organic phase is washed twice with 50ml of a 10% aqueous solution of NaOH each time and then three times withapproximately 50 ml of H₂O each time. The organic phase is dried withNa₂SO₄ and the volatile constituents are evaporated off in vacuo(approximately 10⁻² torr), yielding a pulverulent orange-red solid thatis insoluble in H₂O and hexane and relatively readily soluble in THF,CHCl₃ and CH₂Cl₂.

EXAMPLE A3

[0043] Preparation of Compound 10.

[0044] In a 500 ml Schlenk tube, 29.62 g (168.3 mmol) of4-hydroxy-TEMPO, compound 3, are dissolved in 200 ml of THF, and then5.0 g (208 mmol) of NaH are added thereto. The reaction mixture isstirred at room temperature for 12 hours and then added dropwise to asolution of 5 g (43.1 mmol) of poly(dichlorophosphazene), compound 9, in100 ml of THF. The reaction mixture is stirred for 12 hours at roomtemperature and subsequently heated under reflux for two hours, thenconcentrated to approximately 10% of its volume and poured intoice-water. The precipitated polymer is removed by filtration and treatedwith ice-water again. The salmon-coloured, pulverulent precipitate isremoved by filtration and then washed with a mixture of THF and H₂O(20/80) and subsequently with hexane. The resulting powder is dried invacuo for approximately 12 hours, yielding 16 g (95.7%) of product,compound 10; m.p. >180° C. Compound 10 is soluble in CH₂Cl₂, CHCl₃,acetone, THF and toluene; M_(w) approximately 25000.

EXAMPLE A4

[0045] Preparation of Compound 12:

[0046] In a 500 ml Schlenk tube, 7 g (40.63 mmol) of 4-hydroxy-TEMPO,compound 3, are dissolved in 120 ml of DMF or THF (freshly distilled).At 0° C., 1.6 g (66.67 mmol) of NaH are added to the solution. The batchis heated to room temperature and then stirred for 1 hour. The reactionsolution is subsequently cooled to 0° C. in an ice-bath and 3.5 g ofpolymer (Merrifield polymer from Fluka, 200-400 mesh, 1% divinylbenzene,1.7 mmol of Cl/g) are added thereto. The batch is stirred for 30 minutesat 0° C. and then heated to room temperature and stirred for from 1 to 4days. The batch is subsequently diluted with ice-water, stirred andfiltered. The residue is washed with ice-water until the filtrate iscolourless. The product is then suspended in toluene and stirred forfrom 1 to 2 hours in order to remove non-fixed 4-hydroxy-TEMPO.Filtration is then carried out again and the yellow powder is dried in astream of air.

[0047] The powder contains 0.9 mmol of N-oxyl/g.

EXAMPLES B Oxidation of Alcohols

[0048] General procedure for the oxidation of a primary or secondaryalcohol

[0049] a) Preparation of the NaOCl/NaHCO₃ solution:

[0050] 4 ml of a saturated solution of NaHCO₃ are mixed with 2 ml of anNaOCl solution (13-14%). The solution is stored in a sealed bottle at 0°C.

[0051] b) Oxidation procedure:

[0052] 1.0 g of the alcohol and 0.25 g of the compound (12) from ExampleA4 are introduced into a 250 ml round-bottomed flask and then suspendedin a mixture of 5 ml of acetone and 15 ml of toluene. The batch isstirred vigorously for from 5 to 10 minutes at room temperature untilthe alcohol has dissolved and the resin is swollen. The reaction vesselis cooled to 0° C. With vigorous stirring, 6 ml of the NaOCl/NaHCO₃solution prepared in 1) are added and the batch is stirred for 0.5 hoursat from 0 to 5° C. The ketone is obtained in almost quantitative yieldafter conventional working up.

[0053] c) Recovery of the catalyst:

[0054] If the catalyst is to be used in a plurality of reactionsdirectly following one another, then at the end of each reaction thecatalyst is removed by filtration (G3 frit), briefly washed with acetoneand immediately re-used. After having been used ten times, no loss ofactivity can be detected. The catalytic activity of the compound (12)can also be maintained following storage. For that purpose thefiltered-off catalyst is washed repeatedly with acetone/toluene, thenwith water, again with acetone and finally with acetone/toluene (removalof NaOCI, starting material and product). Storage is in the moist statein a securely sealed container.

EXAMPLES B1 and B2

[0055] Oxidation of Simple Alcohols:

[0056] The experiments are carried out as described in the generalprocedure. The α-hydroxy-ketone 14 is obtained from 13, and the acetone18 from isopropanol 17, in almost quantitative yield.

EXAMPLE B3

[0057] Preparation of α-Hydroxyacetophenone from Phenylglycol:

[0058] Phenylglycol 19 is reacted as described in the general procedure,with NaOCl in the presence of 5% by weight of 12 as catalyst, to formα-hydroxyacetophenone (20). Product 20 is isolated in almostquantitative yield in the form of a crystalline solid.

EXAMPLE B4

[0059] Preparation of Acetylacetone:

[0060] 1.0 g of alcohol 21 and 0.25 g of compound 12 are introduced intoa 250 ml round-bottomed flask and then 20 ml of toluene are addedthereto. The reaction vessel is subsequently cooled to 0° C. Withvigorous stirring, 12 ml of the above-described NaOCl/NaHCO₃ are addedand the batch is stirred at from 0 to 5° C. for ½ hour. The 1,3-diketone22 is obtained as reaction product in almost quantitative yield.

EXAMPLE B5

[0061] Preparation of 2,2,4,6-tetramethyl-1,3-dioxane (23):

[0062] The reaction is carried out as described in Example 4, exceptthat it is carried out in a mixture of 15 ml of toluene and 5 ml ofacetone instead of with 20 ml of toluene.2,2,4,6-Tetramethyl-1,3-dioxane (23) is obtained as reaction product inalmost quantitative yield according to gas chromatography.

EXAMPLE 6

[0063] Preparation of 2-ethyl-2,4,6-trimethyl-1,3-dioxane (24):

[0064] The reaction is carried out as described in Example B4, exceptthat a mixture of 15 ml of toluene and 5 ml of 2-butanone is usedinstead of 20 ml of toluene. 2-Ethyl-2,4,6-trimethyl-1,3-dioxane (24) isobtained as reaction product in almost quantitative yield.

EXAMPLE B7

[0065] Preparation of tetrahydropyran-2-ol (21) andtetrahydropyran-2-one (22)

[0066] 1,5-Pentanediol 25 is oxidised as described in Example B4 withbasic NaOCl in the presence of compound 12 as catalyst, except that theoxidising agent, sodium hypochlorite (13% active chlorine), is usedstoichiometrically. After a reaction time of 30 minutes, a mixture of75% compound 26 and 25% compound 27 is obtained.

EXAMPLE B8

[0067] Preparation of tetrahydropyran-2-one (27)

[0068] The mixture of 26 and 27 prepared in Example B7 is reacted, asdepicted, with excess NaOCI solution buffered to pH 9.0-9.5, 26 beingoxidised completely to 27.

EXAMPLE B9

[0069] Preparation of 2-(5-hydroxy-pentyloxy)-tetrahydropyran (26)

[0070] The above-depicted reaction is carried out with a fourfold excessof diol 25 relative to NaOCl. Conventional working up yields a mixtureof 50% acetal 28 and 50% tetrahydropyran-2-ol 26.

EXAMPLE B10

[0071] Preparation of Benzil (29) from Benzoin:

[0072] 5.0 g (23.5 mmol) of benzoin (28) are reacted as described in thegeneral procedure with sodium hypochlorite in the presence of 1 g ofcompound 12 at from 0 to 5° C. in 50 ml of toluene/acetone 3:1. Duringthe hypochlorite addition, the solid initially present in the reactionmixture dissolves. When the addition is complete, the batch is stirredfor 45 minutes. Monitoring by thin-layer chromatography indicatescomplete and selective conversion. Conventional working up andsubsequent recrystallisation of the crude product from n-hexane yields4.6 g of benzil (29) (93% of theory).

What is claimed is:
 1. A process for the selective oxidation of alcoholsto ketones or to aldehydes by means of an alkali hypohalite underalkaline conditions, which comprises carrying out the oxidation in thepresence of a heterogeneous oxidation catalyst that is insoluble in thereaction medium and is selected from the group comprising the compoundsof formula (I), (II), (III)

(III), wherein n is a number from 3 to 3000; or a4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl that is 4-oxy-bound to aMerrifield polymer.
 2. A process according to claim 1, which comprisesusing as alkali hypohalite LiOCl, NaOCl, KOCl, LiOBr, NaOBr or KOBr. 3.A process according to claim 1, which comprises using a4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl that is 4-oxy-bound to aMerrifield polymer.
 4. A process according to claim 1, which comprisesadding the heterogeneous oxidation catalyst in an amount of from 0.1 to20% by weight, based on the alcohol used.
 5. A process according toclaim 1, which comprises using a two-phase solvent system in which onephase is aqueous and comprises the oxidising agent.
 6. A processaccording to claim 1, which comprises carrying out the reaction at atemperature of less than 10° C.
 7. A compound of formula II or IIIaccording to claim
 1. 8. The use of a compound of formula (I), (II),(III), or a 4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl 4-oxy-bound to aMerrifield polymer, as catalyst for the selective oxidation of alcoholsto ketones by means of an alkali hypohalite under alkaline conditions.